Disease control in patients with non‐small cell lung cancer using pemetrexed: Investigating the best treatment strategy

Abstract Background Pemetrexed (PEM) is the primary chemotherapy for non‐small cell lung cancer (NSCLC), showing potential for long‐term disease stability in certain cases. However, studies examining disease control with PEM therapy are lacking. This study aimed to pinpoint clinical traits in patients with NSCLC responding well to PEM therapy, predict factors influencing disease control, and suggest optimal treatment approaches. Methods A retrospective analysis of patients with NSCLC treated with PEM was performed to compare patients who achieved disease control after treatment with those who did not. Results Of 73 patients, 56 (76.7%) achieved disease control with PEM therapy. In the disease control group, a significantly higher proportion of patients exhibited good performance status (PS) and received PEM doses without reduction after the second cycle. Multivariate analysis identified bevacizumab (Bev) noncompliance, PEM dose reduction, and thyroid transcription factor‐1 (TTF‐1) negativity as significant independent risk factors for disease progression during PEM therapy. Additionally, overall survival was significantly longer in the disease control group (p < 0.001). Conclusions Our findings indicated that maintaining the dose of PEM after the second treatment cycle in patients with NSCLC, along with concurrent use of Bev and the presence of TTF‐1 positivity, could enhance disease control rates and extend survival.

This study aimed to pinpoint clinical traits in patients with NSCLC responding well to PEM therapy, predict factors influencing disease control, and suggest optimal treatment approaches.This study compared patients with NSCLC treated with PEM therapy who achieved disease control with those who did not.

METHODS
Patients with advanced-stage (stage IIIB and IV, postoperative recurrence) NSCLC treated with PEM between August 2012 and December 2022 were retrospectively identified.
Data on age, sex, smoking history, performance status (PS), lung cancer histology, tumor proportion score (TPS), EGFR gene mutations, ALK rearrangements, ROS1 gene rearrangements, and clinical stage were collected during PEM therapy.
Responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1).Patients with partial response (PR) and stable disease (SD) were classified into the disease control group (n = 56), whereas patients with progressive disease (PD) were classified into the disease progression group (n = 17).Clinical information between the two groups was compared.
This study aimed to determine the effects of PEM therapy on disease control.Patients who received PEM plus immune checkpoint inhibitors were excluded from the study.

Statistical analysis
All analyses were performed using the statistical software SPSS 26.0 (SPSS Inc.).Statistical significance was set at p < 0.05 (two-tailed).All categorical variables were analyzed using the chi-square test, whereas those with a predicted frequency below five were analyzed using Fisher's exact probability test.A t-test without correspondence was used to compare the means of continuous variables between the two groups.A multivariate analysis was performed using logistic regression.
Survival curves were generated using the Kaplan-Meier method, and analyses were performed from the start of lung cancer treatment until death or the end of treatment.Survival analysis was performed up to mid-December 2023.
The log-rank test was employed to assess survival differences in response to PEM therapy.Statistical significance was considered when the risk rate was below 5%.This study was approved by the Review Committee of Kanazawa Medical University Hospital (approval no.: C057).

Study cohort
A total of 73 patients were identified.A total of 11 patients in the study received PEM monotherapy: four (36.4%) patients achieved PR, four (36.4%) had SD, and three (27.3%)experienced PD.The response and disease control rates were 36.4% and 72.7%, respectively.A total of 29 patients received carboplatin (CBDCA) + PEM therapy: 11 (37.9%)patients demonstrated a PR, eight (27.6%) had SD, and 10 (34.5%) showed PD.The response and disease control rates were 37.9% and 65.5%, respectively A total of 33 patients received platinum + PEM + bevacizumab (Bev) therapy: 13 (39.4%)patients achieved PR, 16 (48.5%)had SD, and four (12.1%) experienced PD.The response and disease control rates were 37.9% and 87.9%, respectively.No patients received PEM + Bev therapy as initial therapy.Disease control was achieved in 56 (76.7%) patients following PEM therapy (disease control group), whereas 17 (23.3%)were classified in the disease progression group.
The patient characteristics are presented in Table 1.Patients with good PS were significantly more prevalent in the disease (p = 0.005).After the second cycle, the dose of PEM was lowered in 10 patients, with nine of them undergoing a dose reduction during the second cycle and one during the third cycle.The reasons for the PEM dose reduction were thrombocytopenia (grade 4), anorexia (one grade 3 and four grade 2), WBC reduction (two grade 2), and neutropenia (one grade 4 and one grade 3).In contrast, more patients in the disease progression group received a reduced PEM dose after the second cycle (p < 0.001).The duration of PEM therapy was significantly longer in the disease control group (13.3 cycles vs. 2.1 cycles, p < 0.001).
Patients who received PEM therapy in combination with a platinum agent did not differ significantly between the two groups.Similarly, patients who received PEM with Bev did not differ significantly between the two groups.Moreover, age, sex, smoking history, programmed death ligand 1 expression, TTF-1, driver gene mutations, clinical stage, and treatment duration showed no significant differences between the two groups.
In this study, the rate of discontinuation of PEM therapy owing to adverse events was 17.8% (13/73).Table 2 presents the characteristics of patients who ceased PEM therapy due to adverse events.Of these adverse events, five were classified as grade 3, whereas the remaining eight were grade 2, all resolved solely by discontinuing PEM.Among these patients, three underwent PEM dose reduction due to side effects, specifically fatigue (grade 2) and decreased white blood cell (WBC) count (grade 2 in one patient and grade 4 in another).However, patients in Cases 2 and 5 continued PEM treatment with dose reduction.Finally, the patient in Case 2 had PEM treatment interrupted owing to the development of grade 2 conjunctivitis, whereas the patient in Case 5 faced interruption due to grade 3 renal dysfunction.Case 3 patient's PEM dose was reduced and continued owing to fatigue; however, the patient's symptoms did not improve, and treatment was discontinued by the attending physician after the 10th cycle of PEM therapy.
The survival curves for the disease control and disease progression groups are shown in Figure 1.A statistically significant survival benefit was observed in the response group (p < 0.001, log-rank test).

DISCUSSION
In this study, the PEM dose reduction after the second cycle was identified as a significant predictor of disease progression.Furthermore, the duration of PEM therapy was significantly longer in the disease control group, confirming that maintaining treatment intensity by avoiding PEM dose reduction after the second cycle of PEM therapy may contribute to disease control and prolonged survival.
In this study, 10 patients were identified who had reduced PEM therapy.Among them, one experienced a serious side effect (grade 4 thrombocytopenia), and the remaining nine had mild side effects, such as a decrease in WBC count and anorexia of grade 3 or less, suggesting that the combination of G-CSF preparations 20,21 and supportive care [22][23][24] could have allowed continuation of PEM therapy without dose reduction.However, the study as a whole found that 13 patients discontinued PEM therapy due to side effects (Table 2).Although no serious side effects of grade 4 or higher were observed, two patients developed pneumonia, and two experienced worsening renal function.
PEM can cause drug-induced lung injury at a frequency of 0.8%-3.5%, 1,25and deaths have been reported. 26Therefore, discontinuation of PEM should be considered at the onset of pneumonia, even in mild cases.Similarly, the risk of serious hematologic toxicity of PEM is increased in renal dysfunction. 27,28Therefore, treatment with PEM is contraindicated in patients with a creatinine clearance of <45 mL/ min. 29When such side effects occur, appropriate dose reduction or discontinuation of PEM may be necessary.However, the extent to which continued treatment without PEM dose reduction, with appropriate management such as concomitant supportive care, contributes to prolonged survival needs to be evaluated in future studies.Continued maintenance therapy after primary therapy for patients with nonsquamous NSCLC is now the standard of care.Three maintenance options after induction chemotherapy are available in clinical practice: Bev monotherapy, PEM monotherapy, or PEM + Bev therapy.However, an optimal maintenance strategy has not yet been determined. 32his study found that the combination of Bev predicted disease control in PEM therapy.The combination of Bev + PEM improves PFS and overall survival (OS) more than PEM monotherapy. 33herefore, in patients for whom Bev is indicated, the combination of Bev should be considered in PEM maintenance therapy.However, the addition of Bev to PEM does not improve the prognosis in elderly patients. 34Additionally, a higher incidence of adverse effects has been reported with PEM + Bev maintenance therapy compared to PEM monotherapy. 35,36Moreover, real-world clinical practice includes patients for whom Bev is not applicable because of bleeding, renal dysfunction, arterial thrombosis, hypertensive crisis, poor wound healing, or gastrointestinal perforation. 37Thus, precise case selection is important for Bev combination therapy because of concerns regarding elderly patients and increased adverse effects.
In this study, TTF-1 negativity was a predictor of disease progression following PEM therapy.9][40][41] This study indicated that TTF-1 negativity was associated with disease progression in patients with lung cancer treated with PEM.Therefore, alternative treatment options should be considered for patients with TTF-1-negativity instead of PEM.
This study had several limitations.First, it was a singlecenter retrospective study, potentially leading to bias in patient selection and data collection.The majority of patients were evaluated for response approximately 6-8 weeks after PEM therapy.However, due to its retrospective nature, these intervals were not as precisely defined as those in prospective studies.Notably, four patients in the disease progression group underwent an early CT after one cycle of PEM therapy to evaluate lesions 3 weeks posttreatment due to suspected disease progression.
Additionally, few patients in this study tested positive for ALK and ROS1 gene rearrangements (three patients each).Particularly, the absence of patients with positive ALK gene rearrangements in the advanced disease group precluded their inclusion in the multivariate analysis.
Therefore, the findings of this study might be affected by insufficient statistical power to detect differences in ALK and ROS1 gene rearrangements.Future research should involve larger multicenter studies to mitigate this issue.Although the results of this study are preliminary, they do suggest an optimal treatment approach using PEM therapy for patients with NSCLC in real-world clinical practice.
We believe that the results reported in this study will contribute to advancing clinicians' understanding of personalized treatment approaches in managing patients with NSCLC.
Second, the treatment protocols in this study, such as PEM reduction after the second cycle or concomitant Bev use, were not clearly defined and left to the discretion of attending physicians, potentially introducing bias among the study groups.
In this study, patients with a good PS were particularly numerous in the disease control group.Some patients in the disease control group may have responded to PEM therapy due to their good general condition, which cannot be dismissed.Future studies will require larger, prospective, F I G U R E 1 Overall survival in the disease control and the disease progression groups.The median survival in the disease control group was NA, whereas it was 24.4 months in the disease progression group, with a significant difference (log-rank test, p < 0.001).NA, not applicable.
multicenter studies to effectively address confounding factors and ascertain whether PEM therapy, particularly in combination with Bev and continued without dose reduction post the second cycle, genuinely exerts diseasecontrolling effects.
In conclusion, the results suggest that in patients with TTF-1-negative NSCLC, continuing PEM therapy without dose reduction after the second cycle, combined with bevacizumab, improve disease control and prolong maintenance treatment and survival.
T A B L E 1 Comparison of patient characteristics between response and nonresponse groups.Patients with PEM therapy discontinued due to adverse effects.Univariate and multivariate analyses of risk factors for disease progression in patients with NSCLC treated with PEM therapy.